a) Field of the Invention
The present invention relates to methods of treating disease with heteroaryl-aryl ureas which are antagonists of the insulin growth factor-1 receptor. In particular, the invention relates to methods of inhibiting tumor growth and methods of treating cancer.
b) Description of Related Art
A major feature of malignant cells is the loss of control over one or more cell cycle elements. These elements range from cell surface receptors to the regulators of transcription and translation (Hunter, Cell, 64:249-70(1991); Cantley et al., Cell, 64:281-302 (1991); Aaronson, Science, 254:1146-51 (1991); Hitwell et al., Science 266:1821-8 (1994); Baserga, Cell, 79:927-30 (1994)), including the insulin-like growth factors, insulin growth factor-1 (IGF-1) and insulin growth factor-2 (IGF-2). The insulin growth factor system consists of families of ligands, insulin growth factor binding proteins, and receptors. A major physiologic role of the IGI-1 system is the promotion of normal growth and regeneration (Lowe, in Insulin-Like Growth Factors: Molecular and Cellular Aspects, LeRoith, D., ed., Boca Raton: CRC Press, 1991:49; Mathews et al., Endocrinology, 123:2827-33 (1988); Lynch et al., J. Clin. Invest., 84:640-6 (1989)). The cloning of the insulin growth factor-1 receptor (IGF-1R) (Ullrich et al., EMBO J., 5:2503-12 (1986)) allowed for the definitive demonstration that the activation of an overexpressed IGF-1R can initiate mitogenesis (Pietrzkowski et al., Cell Growth Diff., 3:199-205 (1992)) and promote ligand-dependent neoplastic transformation (Kaleko et al., Mol. Cell Biol. 10:464-73 (1990)). Furthermore, IGF-1R plays an important role in the establishment and maintenance of the malignant phenotype (Insulin-Like Growth Factors: Molecular and Cellular Aspects, LeRoith D, ed., Boca Raton: CRC Press, (1991); Masters et al., Ann. NY Acad. Sci., 692: 89-101 (1993); Humbel, Eur. J. Biochem., 190:445-62 (1990); Sara et al., Physiol. Rev. 70:591-614 (1990); Sussenbach, Prog. Growth Factor Res., 1:33-40 (1989); Bondy et al., Ann. Intern. Med., 120:593-602 (1994)).
IGF-1R is synthesized as a single polypeptide chain, which is then glycosylated and cleaved into separate alpha and beta subunits. The receptor exists as a heterodimer, with several disulfide bridges. The ligand-binding domain is located on the extracellular alpha subunit. Approximately one-third of the beta-subunit is extracellular and is connected to the intracellular portion by a single transmembrane domain. The tyrosine kinase catalytic site and the ATP binding site are located on the cytoplasmic portion of the beta-subunit.
Unlike the epidermal growth factor (EGF) receptor, no mutant oncogenic forms of the IGF-1R have been identified. However, several oncogenes have been demonstrated to affect IGF-1 and IGF-1R expression (Ullrich et al., EMBO J., 5:2503-12 (1986)). It has been shown that cells with disrupted IGF-1R genes will not grow in serum-free medium supplemented with growth factors. In addition these cells cannot be transformed by transfection with SV40T antigen or ras, agents that efficiently transform corresponding wild-type cells (Sell et al., Mol. Cell Biol., 14:3604-12 (1994); Sell et al., Proc. Natl Acad. Sci. USA, 90:11217-21 (1993)).
The correlation between a reduction of IGF-1R expression and resistance to transformation has been seen in several other systems as well. Prager et al. inhibited the growth and transformation of rat-I fibroblasts by introduction of a dominant negative mutant of the IGF-1R (Prager et al., Proc. Natl. Acad. Sci. USA., 91:2181-5 (1994)). Others have used an antisense strategy to reduce production of IGF-1R. Exposure of cells to the mRNA antisense to IGF-1R RNA, prevents soft agar growth of several human tumor cell lines (Resnicoff et al., Cancer Res., 55:2463-9 (1995); Resnicoff et al., Lab. Invest., 69:756-60 (1993); Resnicoff et al., Cancer Res., 54:4848-50 (1994); Shapiro et al., J Clin. Invest., 94:1235-42 (1994)).
It is now established that a major mode of tumor survival is escape from apoptosis (Fisher, Cell, 78:539-42 (1994)). IGF-1R abrogates progression into apoptosis, both in vivo and in vitro (Kulik et al., Mol. Cell. Bio., 17: 1595-1606 (1997); Lamm et al., Cancer Res., 58:801(1998)). It has also been shown that a decrease in the level of IGF-1R below wild-type levels causes apoptosis of tumor cells in vivo (Resnicoff et al., Cancer Res., 55:2463-2469 (1995); Resnicoff et al., Cancer Res., 55:3739-3741 (1995)). The ability of IGF-1R disruption to cause apoptosis appears to be diminished in normal, non-tumorigenic cells (Barega, Trends Biotechnol., 14:150-2 (1996)).
Hence, the ligand-activated IGF-1R appears to have at least three important functions. First, it is required for optimal growth, although some growth occurs even in its absence. Second, IGF-1R is also obligatory for the establishment and maintenance of the transformed phenotype and for tumorigenesis for several types of cells. It also appears to protect cells from apoptosis. These features make IGF-1R an attractive target for therapeutic interventions against abnormal growth.
To date, there are few reports of compounds that are selective IGF-1 receptor antagonists. Parrizas et al. describe tyrphostins that had some efficacy in vitro and in vivo (Parrizas et al., Endocrinology, 138:1427-33 (1997)). These compounds were of modest potency and selectivity over the insulin receptor.
Another family of compounds, heteroaryl-aryl ureas, are ubiquitous in the literature. They have a long history of biological applications. Recently, a number of heteroaryl-aryl ureas have been described as 5HT2c receptor antagonists as treatments for CNS disorders (WO 94/18170; WO 95/01976; WO 94/22871; WO 94/04533; WO 94/14801; WO 93/18028). In addition, they have been reported as ligands for the benzodiazepine receptor (Shindo et al., Heterocycles, 1989, 29, 899), inhibitors to fat metabolism (DE 29284485), anti-inflammatories (EP 123146), pesticides (JP 04178362) and some derivatives as antimicrobials (Patel et al., J. Inst. Chem.(lndia), 1989, 61, 93). As such, several reports to the preparation of these compounds, both on solid phase and in solution have been reported (Buckman et al., Tet. Lett., 1996, 37, 4439; Stewart et al., J. Med. Chem., 1970, 13, 762)
The invention relates to the use of heteroaryl-aryl urea compounds which have been found to be antagonists of the IGF-1 receptor. These compounds, or salts thereof, are suitable for the treatment of essentially any mammalian disease condition in which the IGF-1 receptor plays an active role and where suppressing the activity of IGF-1R ameliorates the disease condition. The generic formula of the heteroaryl-aryl urea compounds useful in the present invention is as follows: 
wherein
R1-R5 are, independently, hydrogen, lower alkyl, substituted lower alkyl, hydroxyl, lower alkoxy, lower acyl, lower alkenyl, lower alkylthio, lower alkynyl, halo, C(O)NR7R8, COOR9, NR10R11, a heterocyclic residue, aryl, aralkyl, cyano or nitro, any two adjacent substituents R1-R5 optionally together forming a lower alkylenedioxy,
R6 is a heterocyclic residue,
R7, R8, R9 are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, aralkyl, or a heterocyclic residue,
R10, R11 are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, lower acyl, aralkyl, or a heterocyclic residue, and
R7 and R8 or R10 and R11 together with the nitrogen may form a heterocyclic residue.
In one embodiment, R6 is quinolinyl, optionally substituted.
One embodiment of the invention provides for a method of inhibiting the activity of the insulin-like growth factor-1 receptor in a mammalian cell. This method comprises administering an effective amount of a compound of formula I to the mammalian cell.
Another embodiment of the invention provides for a method of inhibiting the growth of a cell in a mammal. This method involves administering a compound of formula I to the cell in an amount sufficient to inhibit the growth of the cell.
Still another embodiment of the invention provides for a method of promoting apoptosis in a tumor cell, or more specifically, inhibiting the ability of a mammalian cell to escape from apoptosis. In this method, a compound of formula I is administered to the tumor cell in an amount sufficient to promote apoptosis.
The present invention also provides for a method of using a heteroaryl-aryl urea compound for the treatment of cancer. A method for treating cancer in a mammal is provided where a compound of formula I is administered to the mammal in a therapeutically effective, substantially non-toxic amount.
It is further contemplated by the present invention that the heteroaryl-aryl urea compounds of formula I may be used to inhibit an abnormal growth in a mammal. This method requires that a compound of formula I be administered to the abnormal growth of the mammal in a therapeutically effective, substantially non-toxic amount.
In a still further embodiment of the invention, a compound of formula I is used to treat an IGF-1R-related condition in a mammal by inhibiting the activity of IGF-1R in a tissue of the mammal his method comprises administering a compound of formula I to the tissue of the mammal in a therapeutically effective amount.